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Strong Immunogenicity of Heterologous Prime-Boost Immunizations with the Experimental Vaccine Grad-COV2 and Bnt162b2 Or Chadox1-Ncov19

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Strong Immunogenicity of Heterologous Prime-Boost Immunizations with the Experimental Vaccine Grad-COV2 and Bnt162b2 Or Chadox1-Ncov19 medRxiv preprint doi: https://doi.org/10.1101/2021.06.22.21258961; this version posted June 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . Strong immunogenicity of heterologous prime-boost immunizations with the experimental vaccine GRAd-COV2 and BNT162b2 or ChAdOx1-nCOV19 Chiara Agrati1†*, Stefania Capone2†, Concetta Castilletti1, Eleonora Cimini1, Giulia Matusali1, Silvia Meschi1, Eleonora Tartaglia1, Roberto Camerini2, Simone Lanini1, Stefano Milleri3, Stefano Colloca2, Alessandra Vitelli2, Antonella Folgori2 Affiliations: 1Istituto Nazionale per Le Malattie Infettive Lazzaro Spallanzani IRCCS; Rome, Italy. 2ReiThera Srl; Rome, Italy. 3Centro Ricerche Cliniche di Verona srl; Verona, Italy. †These authors contributed equally to this work *Corresponding author. Email: [email protected] Running title: Approved vaccines boost GRAd-COV2-primed immune response Abstract Here we report on the humoral and cellular immune response in eight volunteers who autonomously chose to adhere to the Italian national COVID-19 vaccination campaign more than 3 months after receiving a single administration GRAd-COV2 vaccine candidate in the context of the phase 1 clinical trial. We observed a clear boost of both binding/neutralizing antibodies as well as T cell responses upon receipt of the heterologous BNT162b2 or ChAdOx1-nCOV19 vaccines. These results, despite the limitation of the small sample size, support the concept that a single-dose of an adenoviral vaccine may represent an ideal tool to effectively prime a balanced immune response, which can be boosted to high levels by a single dose of a different vaccine platform. Main Text During the first year of the COVID-19 pandemic several clinical trials provided evidence of the efficacy of a number of candidate vaccine against SARS-CoV-2 1. However, with new COVID- 19 waves and global vaccine shortages the benefits of mixing two vaccines into one heterologous vaccination regimen are apparent and point towards a possibility of implementing this regimen to 2 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. medRxiv preprint doi: https://doi.org/10.1101/2021.06.22.21258961; this version posted June 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . reach broad vaccine coverage 2. A heterologous vaccination regimen may also be needed to maintain protective immunity against SARS-CoV-2 over time. Finally, the use of a different vaccine has been suggested as a way to overcome hesitancy in persons who received a first dose of an adenoviral vectored vaccine for which safety concerns were raised. In fact, several European countries, such as Spain and Germany, are recommending a booster dose with mRNA vaccines to people under the age of 60 that received primary vaccination with Vaxzevria. There is experimental evidence suggesting that heterologous vaccination improves the immune responses 3 and indeed this strategy has been proposed in vaccination against other viruses 4 and cancer 5. Preclinical data in mice confirm the immunological benefit of combining COVID-19 vaccines from different platforms 6,7 and several clinical trials are presently underway to test the safety and immunogenicity of this strategy for SARS- CoV2 infection. We recently concluded a Phase 1 study to assess safety and immunogenicity of a single-dose regimen of a gorilla adenovirus vectored vaccine (GRAd-COV2) in younger (aged 18-55) and older (65-85) volunteers 8. The results showed good safety of the GRAd-COV2 vaccine and induction of both humoral (binding as well as neutralizing) and Th1 skewed cell-mediated immune response. At the final 24 weeks monitoring visit, eight enrolled volunteers reported that, outside the study procedures and in the context of the Italian National Vaccination Campaign (Table 1), they received either a full course (n=3) or only the first dose of BNT162b2-mRNA (n=3), or one dose of ChAdOx1 (n=2). These vaccinations occurred in a time frame between 14 and 24 weeks after the GRAd-COV2 study vaccination, and therefore side effects were not collected. These subjects provided blood samples to perform protocol defined laboratory test on anti- SARS-CoV2 humoral and cell-mediated immune response. In response to the heterologous vaccines, the levels of anti-Spike binding antibody levels measured at week 24 were greatly amplified compared to week 12, and exceeded the peak level recorded in each individual around week 4-8 post GRAd-COV2 vaccination (Figure 1), with no major differences in subjects receiving one or two doses of the heterologous vaccine. The only exception is volunteer F, who received the first BNT162b2 only 3 days before the week 24 visit, whose Spike Ab response slightly contracted from the last week 12 visit. Similarly, neutralizing titers at week 24 (MNA90) were potently boosted in all volunteers except F, and clearly exceeded those measured at study week 4. T cell responses were also assessed throughout the study visits by IFNγ ELISpot 2 medRxiv preprint doi: https://doi.org/10.1101/2021.06.22.21258961; this version posted June 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . on frozen PBMC. Interestingly, the strong T cell response induced by GRAd-COV2 was further boosted with respect to both the peak and/or the week 12 levels in two volunteers receiving two mRNA doses (A and B), one receiving one mRNA dose (E) and in two volunteers receiving one ChAdOx1 dose (G and H). In the remaining subjects receiving one (D) or two mRNA doses (C) the T cell responses at week 24 were maintained at the same level as three months before, but did not further contract as observed in volunteer F. This report has obvious limitations in the number of subjects and in the lack of safety data of the heterologous administration. Nevertheless, our observations suggest that the immune responses induced by the single-dose GRAd-COV2 vaccination can be effectively boosted also by a single heterologous vaccination with two approved vaccines, amplifying both antibody and T cell response. These data are confirmatory of recently disclosed results from a study of safety and immunogenicity of homologous and heterologous immunization with ChAdOx1-nCoV19 and BNT162b2 9. Overall, these evidences support the concept that a single-dose of an adenoviral vaccine, which is cheap and easy to deploy in a pandemic setting, represents a good tool to effectively prime the immune system, which can be boosted afterwards by a single dose of a different vaccine platform, reaching high levels of immune responses. As preclinical and clinical evidence suggest 6,9, keeping adenoviral vectored vaccines as part of heterologous vaccination regimens may be the key for optimal induction and persistence of T cell responses, a feature that may confer cross-protection in the context of already circulating and newly emerging SARS-CoV-2 variants 10. Further prospective and controlled investigations are mandatory to confirm these data and to evaluate the impact of age and the optimal timing between prime and boost as well as the order of administration of the heterologous vaccines. 2 medRxiv preprint doi: https://doi.org/10.1101/2021.06.22.21258961; this version posted June 28, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license . References 1 Pormohammad, A. et al. Efficacy and Safety of COVID-19 Vaccines: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Vaccines (Basel) 9, doi:10.3390/vaccines9050467 (2021). 2 Wolff, J. et al. Ethical and policy considerations for COVID-19 vaccination modalities: delayed second dose, fractional dose, mixed vaccines. BMJ Glob Health 6, doi:10.1136/bmjgh-2021-005912 (2021). 3 Lu, S. Heterologous prime-boost vaccination. Curr Opin Immunol 21, 346-351, doi:10.1016/j.coi.2009.05.016 (2009). 4 Venkatraman, N. et al. Safety and Immunogenicity of a Heterologous Prime-Boost Ebola Virus Vaccine Regimen in Healthy Adults in the United Kingdom and Senegal. J Infect Dis 219, 1187-1197, doi:10.1093/infdis/jiy639 (2019). 5 Ring, S. S. et al. Heterologous Prime Boost Vaccination Induces Protective Melanoma- Specific CD8(+) T Cell Responses. Mol Ther Oncolytics 19, 179-187, doi:10.1016/j.omto.2020.10.001 (2020). 6 He, Q. et al. Heterologous prime-boost: breaking the protective immune response bottleneck of COVID-19 vaccine candidates. Emerg Microbes Infect 10, 629-637, doi:10.1080/22221751.2021.1902245 (2021). 7 Spencer, A. J. et al. Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice. Nat Commun 12, 2893, doi:10.1038/s41467-021-23173-1 (2021). 8 Lanini, S. et al. GRAd-COV2, a gorilla adenovirus based candidate vaccine against COVID-19, is safe and immunogenic in young and older adults. medRxiv, 2021.2004.2010.21255202, doi:10.1101/2021.04.10.21255202 (2021). 9 Hillus, D. et al. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1-nCoV19 and BNT162b2: a prospective cohort study. medRxiv, 2021.2005.2019.21257334, doi:10.1101/2021.05.19.21257334 (2021).
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